Cancer escape is an active process that regulates immune responses employing at least two types of suppressive cells, myeloid-derived suppressive cells (Gr1+ CD11b+ MDSCs) and regulatory T cells (Tregs) (Youn et al., J. Immunol. 181, 5791-5802, 2008; Nagaraj and Gabrilovich, Cancer Res. 68, 2561-2563, 2008; Liu et al., J. Immunol. 178, 2883-2892, 2007; Olkhanud et al., Cancer Res. 69, 5996-6004, 2009). For example, cancer cells produce or induce production of GM-CSF, IL-1β, IL-6 and TGFβ to promote generation of Gr1+ MDSCs and M2 macrophages which, in turn, impair antitumor immune responses and promote metastasis (DuPre et al., Int. J. Exp. Pathol. 88, 351-360, 2007; Danna et al., Cancer Res. 64, 2205-2211, 2004; Sinha et al., J. Immunol. 174, 636-645, 2005). This occurs through direct action or indirectly by activating Tregs.
Tregs, as a key subset of CD4+ T cells that control peripheral tolerance to self- and allo-antigens (Sakaguchi et al., J. Immunol. 155, 1151-1164, 1995), represent a group of regulatory T cells expressing CD25 (IL-2Rα), CTL-associated antigen 4 (CTLA-4), scurfin and importantly a fork-head box P3 (FoxP3) gene product (Fontenot et al., Nat. Immunol. 4, 330-336, 2003). They are responsible for direct or indirect inhibition of T cell responses through the suppression of antigen-presenting cells, such as dendritic cells (Serafini et al., Cancer Immunol. Immunother. 53, 64-72, 2004; Huang et al., Cancer Res. 66, 1123-1131, 2006). To do this, they utilize (Fontenot et al., supra 2003; Zheng et al., J. Immunol. 172, 2778-2784, 2004; Cavani et al., J. Invest Dermatol. 114, 295-302, 2000) cell contact-dependent processes involving FasL/Fas and PD1/B7-H1 (Olkhanud et al., supra, 2009; Phares et al., J. Immunol. 182, 5430-5438, 2009; Probst et al., Nat. Immunol. 6, 280-286, 2005), though the use of secreted suppressive factors such as IL-10, TGF-β, IL-27 and IL-35 have also been reported (Groux et al., Nature 389, 737-742, 1997; Annacker et al., J. Immunol. 166, 3008-3018, 2001; Awasthi et al., Nat. Immunol. 8, 1380-1389, 2007; Collison et al., Nature 450, 566-569, 2007). As a result, Tregs are considered to play a key role in the escape of cancer cells from anti-tumor effector T cells (Ishida et al., Clin. Cancer Res. 9, 3625-3634, 2003; Curiel et al., Nat. Med. 10, 942-949, 2004; Woo et al., J. Immunol. 168, 4272-4276, 2002; Beyer et al., Blood. 106, 2018-2025, 2005). In addition, Tregs play an active role in breast cancer lung metastasis by protecting metastasizing cancer cells from NK cells (Olkhanud et al., supra, 2009).
However, a need remains to identify other regulatory immune cells, and to use these cells for the treatment of immune-mediated disease. In addition, a need remains for inhibiting regulatory immune cells that can inhibit immune-mediated therapy, such as for the treatment of cancer.